Not Applicable
Field of the Inventionxe2x80x94The present invention relates generally to the modification and control of optimal temperatures for enzymes. More particularly, the invention relates to the modification and control of optimal temperatures for enzymes for use in treatments such as thrombolysis.
Background Informationxe2x80x94Organs in the human body, such as the brain, kidney and heart, are maintained at a constant temperature of approximately 37xc2x0 C. Hypothermia can be clinically defined as a core body temperature of 35xc2x0 C. or less. Hypothermia is sometimes characterized further according to its severity. A body core temperature in the range of 33xc2x0 C. to 35xc2x0 C. is described as mild hypothermia. A body temperature of 28xc2x0 C. to 32xc2x0 C. is described as moderate hypothermia. A body core temperature in the range of 24xc2x0 C. to 28xc2x0 C. is described as severe hypothermia.
Hypothermia is uniquely effective in reducing brain injury caused by a variety of neurological insults and may eventually play an important role in emergency brain resuscitation. Experimental evidence has demonstrated that cerebral cooling improves outcome after global ischemia, focal ischemia, or traumatic brain injury. For this reason, hypothermia may be induced in order to reduce the effect of certain bodily injuries to the brain as well as other organs.
Cerebral hypothermia has traditionally been accomplished through whole body cooling to create a condition of total body hypothermia in the range of 20xc2x0 C. to 30xc2x0 C. However, the use of total body hypothermia risks certain deleterious systematic vascular effects. For example, total body hypothermia may cause severe derangement of the cardiovascular system, including low cardiac output, elevated systematic resistance, and ventricular fibrillation. Other side effects include renal failure, disseminated intravascular coagulation, and electrolyte disturbances. In addition to the undesirable side effects, total body hypothermia is difficult to administer.
Catheters have been developed which are inserted into the bloodstream of the patient in order to induce total body hypothermia. For example, U.S. Pat. No. 3,425,419 to Dato describes a method and apparatus of lowering and raising the temperature of the human body. Dato induces moderate hypothermia in a patient using a metallic catheter. The metallic catheter has an inner passageway through which a fluid, such as water, can be circulated. The catheter is inserted through the femoral vein and then through the inferior vena cava as far as the right atrium and the superior vena cava. The Dato catheter has an elongated cylindrical shape and is constructed from stainless steel. By way of example, Dato suggests the use of a catheter approximately 70 cm in length and approximately 6 mm in diameter. However, use of the Dato device implicates the negative effects of total body hypothermia described above.
Due to the problems associated with total body hypothermia, attempts have been made to provide more selective cooling. For example, cooling helmets or head gear have been used in an attempt to cool only the head rather than the patient""s entire body. However, such methods rely on conductive heat transfer through the skull and into the brain. One drawback of using conductive heat transfer is that the process of reducing the temperature of the brain is prolonged. Also, it is difficult to precisely control the temperature of the brain when using conduction due to the temperature gradient that must be established externally in order to sufficiently lower the internal temperature. In addition, when using conduction to cool the brain, the face of the patient is also subjected to severe hypothermia, increasing discomfort and the likelihood of negative side effects. It is known that profound cooling of the face can cause similar cardiovascular side effects as total body cooling. From a practical standpoint, such devices are cumbersome and may make continued treatment of the patient difficult or impossible.
Selected organ hypothermia has been accomplished using extracorporeal perfusion, as detailed by Arthur E. Schwartz, M.D. et al., in Isolated Cerebral Hypothermia by Single Carotid Artery Perfusion of Extracorporeally Cooled Blood in Baboons, which appeared in Vol. 39, No. 3, NEUROSURGERY 577 (September, 1996). In this study, blood was continually withdrawn from baboons through the femoral artery. The blood was cooled by a water bath and then infused through a common carotid artery with its external branches occluded. Using this method, normal heart rhythm, systemic arterial blood pressure and arterial blood gas values were maintained during the hypothermia. This study showed that the brain could be selectively cooled to temperatures of 20xc2x0 C. without reducing the temperature of the entire body. However, external circulation of blood is not a practical approach for treating humans because the risk of infection, need for anticoagulation, and risk of bleeding is too great. Further, this method requires cannulation of two vessels making it more cumbersome to perform particularly in emergency settings. Even more, percutaneous cannulation of the carotid artery is difficult and potentially fatal due to the associated arterial wall trauma. Finally, this method would be ineffective to cool other organs, such as the kidneys, because the feeding arteries cannot be directly cannulated percutaneously.
Selective organ hypothermia has also been attempted by perfusion of a cold solution such as saline or perflourocarbons. This process is commonly used to protect the heart during heart surgery and is referred to as cardioplegia. Perfusion of a cold solution has a number of drawbacks, including a limited time of administration due to excessive volume accumulation, cost, and inconvenience of maintaining the perfusate and lack of effectiveness due to the temperature dilution from the blood. Temperature dilution by the blood is a particular problem in high blood flow organs such as the brain.
Selective organ hypothermia is useful in limiting brain injury after ischemia or traumatic brain injury, as noted above. For example, neurons subjected to ischemia may die. Selective cooling of these neurons, such as by nerve cooling, has been shown to increase the survival rate. Hypothermic temperatures which may be employed include, e.g., 20xc2x0 C. to 35xc2x0 C.
Ischemia is blockage of the arteries that supply blood to a tissue. The blockage itself is referred to as a clot or thrombus and results from the solidification of fibrinogen into fibrin. A stroke is ischemia where the arteries to the brain are blocked. In a stroke, the clot forms in the cerebral or pre-cerebral arteries. This type of blockage may also be caused by a thrombus that breaks free from the heart and flows into an artery through which it cannot pass. In other words, the thrombus gets lodged in the artery.
Clots can be treated in several ways. One way, fibrinolysis, employs enzymes that lyse, or break up and dissolve, the clot. Thrombolysis is fibrinolysis used to treat thrombosed vessels. The enzymes that lyse clots are termed thrombolytics because thrombin is the enzyme that coagulates fibrinogen. Streptokinase(xe2x80x9cSKxe2x80x9d), urokinase (xe2x80x9cUKxe2x80x9d), and tissue plasminogen activator (xe2x80x9ctPAxe2x80x9d) are thrombolytics and are often used in this capacity. These enzymes can be given as drugs by intravenous injection or by intraarterial delivery using a catheter with a fluid outlet port near or at the site of the clot.
Drug administration is occasionally problematic as some sensitive patients encounter adverse reactions to drugs. Moreover, there is a risk of hemorrhage when these drugs are given intravenously. There is a need for a method of lysing clots that does not rely solely or partially on drug administration. There is further a need for a method of lysing clots in which the effects of ischemia on affected cells is minimized.
In some cases, of course, the extent or nature of the clot indicates that drug therapies must be used. The effectiveness of drug therapies is dependent on several factors, including the temperature of the environment in which the drug acts. Thus, there is further a need for a drug therapy which is effective to treat a thrombus and which is also complementary to efforts to reduce ischemia, especially when those efforts employ hypothermia.
In one aspect, the invention relates to a method for substantially reducing the size of a thrombus in a blood vessel. The method includes delivering a heat transfer element to a blood vessel in fluid communication with a thrombosed blood vessel. The temperature of the heat transfer element is adjusted such that the same is sufficient to remove heat from the flowing blood. Heat is transferred from a volume of blood including the thrombus to the heat transfer element. The resultant temperature of the volume may be sufficient to substantially reduce the size of a thrombus. For example, the resultant temperature of the volume may be sufficiently high to substantially enhance plasminogen activation near the thrombus.
Implementations of the invention may include one or more of the following. The temperature of the blood may be adjusted by the heat transfer element to a temperature of between about 30xc2x0 C. and 32xc2x0 C. The temperature sufficient to substantially reduce the size of a thrombus is also sufficient to substantially reduce plasmin inhibitor activity near the thrombus. The temperature of the heat transfer element may be raised from a temperature sufficient to substantially reduce the size of the thrombus to a temperature sufficient to substantially rewarm the volume, and may further be cycled between these temperatures. In this case, the temperature sufficient to reduce the size of the thrombus is between about 25xc2x0 C. and 32xc2x0 C., and the temperature sufficient to substantially rewarm the volume is between about 34xc2x0 C. and 36xc2x0 C.
The delivering and adjusting may further include inserting the heat transfer element into the vessel and cooling the heat transfer element by delivering a working fluid to the heat transfer element. The working fluid may be delivered at a temperature of between about xe2x88x923xc2x0 C. and 1xc2x0 C. The heat transfer element may be inflated with the working fluid, which may be delivered at a pressure of less than 5 atmospheres, such as about 1 to 5 atmospheres.
Turbulence may also be induced in the flowing blood or in the working fluid. Regarding the former, turbulence may be induced with a turbulence intensity of greater than about 0.05. Blood turbulence may be induced in greater than 20% of the period of the cardiac cycle within the carotid artery, such as during the entire period of the cardiac cycle. To induce turbulence in the working fluid, the inflating may include passing the working fluid through a substantially helical-shaped structure. About 75 to 200 watts of heat may be removed from the blood.
In another aspect, the invention relates to a method for dissolving a blood clot. The method includes introducing a catheter having a cooling element into a blood vessel in which a blood clot has formed and disposing the cooling element within the blood vessel such that blood flows past the cooling element to the blood clot. At least a portion of the volume of blood surrounding the blood clot is cooled. Free stream turbulence may be induced in blood flowing over the catheter. The method thus reduces inhibition of anti-clotting enzymes by the cooling.
In yet another aspect, the invention relates to a method of altering the activity of an enzyme present in a flow of blood relative to the activity of the enzyme at a normal blood temperature. The method includes delivering a heat transfer element to the blood flow upstream of the enzyme, adjusting the temperature of the heat transfer element such that the temperature of the heat transfer element is sufficient to alter the temperature of a local portion of the blood flow including the enzyme, and transferring heat between the portion of the blood flow and the heat transfer element. The resultant temperature of the portion of the blood flow is sufficient to substantially alter the enzyme activity within at least the portion of the blood flow.
Implementations of the invention may include extending the technique to stationary volumes of blood or tissue. The adjusting may further include cooling the heat transfer element by delivering a working fluid to the heat transfer element and inducing turbulence within the working fluid or in the flow of blood.
In a further aspect, the invention is related to a method for providing an optimal working temperature for a temperature-specific enzyme with a drug in a blood vessel. The method includes delivering a heat transfer element to a blood vessel, the blood vessel containing a temperature-specific enzyme. The temperature of the heat transfer element is adjusted such that the temperature-specific enzyme is heated to a prespecified temperature range within at least a portion of which the optimal working temperature for a temperature-specific enzyme is attained. The optimal working temperature in the blood vessel is substantially different from the normal body temperature in the blood vessel.
In another aspect, the invention is directed towards a method for selective thrombolysis by selective vessel hypothermia. The method includes introducing a catheter having a heat transfer element into a blood vessel in fluid communication with a thrombosed blood vessel. The heat transfer element is cooled by flowing a working fluid through the heat transfer element. The blood is cooled by flowing the blood past the heat transfer element and inducing free stream turbulence in the blood, such that the blood is cooled to a prespecified temperature range. A thrombolytic drug is then delivered to the blood, the thrombolytic drug having a working temperature within the prespecified temperature range.
Implementations of the invention may include one or more of the following. The drug may be chosen from tPA, urokinase, streptokinase, precursors of urokinase, and combinations thereof. If the drug is tPA, the prespecified temperature range may be between about 30xc2x0 C. to 32xc2x0 C. The blood may then be rewarmed and cycled. If the thrombolytic drug is streptokinase, the prespecified temperature range may between about 30xc2x0 C. and 32xc2x0 C., and the rewarming may raise the blood temperature to about 37xc2x0 C. If the thrombolytic drug is urokinase, the prespecified temperature range may be below about 28xc2x0 C., and the rewarming may raise the blood temperature to about 37xc2x0 C. If the thrombolytic drug is a precursor to urokinase, the prespecified temperature range may be below about 28xc2x0 C., and the rewarming may raise the blood temperature to about 37xc2x0 C.
In yet another aspect, the blood may be warmed instead of cooled. In this case, if the drug is tPA, the prespecified temperature range may be between about 37xc2x0 C. to 40xc2x0 C.
Advantages of the invention include one or more of the following. Clot lysis may be achieved conveniently and selectively, and may be induced without the need for additional anticoagulants. The effects of ischemia are reduced during the procedure, reducing damage to affected cells. In the case where drugs are administered to further treat a thrombus, hypothermia may also be induced as a complementary therapy to reduce the effects of ischemia and to provide neural protection.
The novel features of this invention, as well as the invention itself, will be best understood from the attached drawings, taken along with the following description, in which similar reference characters refer to similar parts, and in which: